Glaucoma is the second leading cause of vision loss worldwide (Quigley, H. A. Br. J Ophthalmol. 80: 389-393 (1996)). By the year 2000, an estimated 66.8 million people will have primary glaucoma and 6.7 million will be bilaterally blind due to this disorder (Quigley, H. A. Br. J. Ophthalmol. 80: 389-393 (1996)). In the United States, glaucoma is the second leading cause of permanent blindness and the leading cause among African Americans(Leske, M. C. Am. J. Epidemiol 118:166-191(1983)). Glaucoma is an optic neuropathy characterized by optic nerve head excavation (cupping) which can lead to loss of peripheral vision and sometimes loss of central vision. While glaucoma is treatable and vision loss can be prevented, once vision loss occurs it is irreversible.
Elevated intraocular pressure (IOP) is a major risk factor for the development of glaucoma, but it is not found in all patients with the disease (Sommer, A. et al., Arch. Ophthalmol. 109: 1090-1095 (1991) and is not included in the definition. The glaucoma associated with elevated IOP is divided into three major categories: open angle, closed angle and developmental. Each of these categories is further divided into primary and secondary forms, and by age of onset.
Recently, genes have been identified which cause juvenile-onset primary open angle glaucoma (MYOC and the GLCIA locus on chromosome 1) (Stone, E. M. et al., Science 275: 668-670 (1997)), PCG (CYPIBI at the GLC3A locus on chromosome 2) (Stoilov, I. et al., Hum. Mol. Genet. 6: 641-647 (1997)), Rieger Syndrome (PITX2 at the RIEG1 locus on chromosome 4) (Semina, E. V. et al., Nat. Genet. 14: 392-399 (1996) and IH (PITX2 at the IRID2 locus on chromosome 4) (Alward, W. L. M. et al., Am. J. Ophthalmol. 125: 98-100 (1998)). MYOC also appears to be involved in approximately 3% of adult-onset open angle glaucoma (Stone, E. M. et al., Science 275: 668-670 (1997)).
Several loci involved in glaucoma or associated phenotypes have been genetically mapped including that of a second PCG locus (GLC3B) to 1p36 (Akarsu, A. N. et al. Hum. Mol Genet. 5: 1199-1203 (1996)), a second Rieger syndrome locus (RIEG2) to 13q14 (Phillips, J. C. et. al., Am. J. Hum. Genet. 59: 613-619 (1996)) and two loci for adult-onset open angle glaucoma (GLCIB and GLCIC) to chromosomes 2 (Stoilova, D et al., Genomics, 36: 142-150 (1996) and 3 (Wirtz, M. K. Am. J. Hum. Genet. 60:296-304 (1997)). In addition, a group of dominant disorders involving changes in the anterior segment of the eye have been mapped to 6p25 (Mears, A. J. et al., Am. J Hum. Genet. 59:1321-1327 (1996); Gould, D. B. et al., Am. J. Hum. Genet. 61:765-768 (1997); Jordan, T. et al., Am. J. Hum. Genet. 61:882-888 (1997); and Graff C. et al., Hum. Genet. 101:130-134 (1997)). These disorders all have glaucoma as part of their phenotype and have beer postulated to be allelic (Jordan, T. et al., Am. J. Hum. Genet. 61:882-888 (1997)).